Retinoic acid-induced abnormal development of hindlimb joints in the mouse

Following a single oral dose of 200 mg/kg of retinoic acid (RA) to pregnant TO mice on day 12 of gestation, fetuses were collected on day 18. RA-treatment resulted in a modest increase in embryo resorption, a significant reduction in fetal body weight and a 96% incidence of limb malformations. Both fore- and hindlimbs were malformed in equal frequency. In this study, only the anomalies of the hindlimbs have been considered. Alizarin stained skeletal preparations revealed a reduction in both length and thickness as well as bowing of the long bones. Agenesis of most of the metatarsals and some toes and/or phalanges was also noted. Paraffin sections cut serially confirmed the gross observations. Additionally, the joint cavities were found to be absent and the cartilaginous ends of the articulating bones were continuous with each other. In some this union was partial and occasionally the joint was only represented by a fine slit. The synovial membrane and other intra-articular structures were either rudimentary or absent. There was a marked reduction in endochondral ossification. Bony union in syndactyly was occasionally observed. These data indicate that a high dose of RA, both inhibits skeletal growth and interferes with the differentiation of the inter-zone mesenchyme, thus resulting in abnormalities of the joints in the TO mouse fetuses.